International Journal of

Environmental Research
and Public Health

Article
Diagnosis of HELLP Syndrome: A 10-Year Survey in
a Perinatology Centre
Kestutis Rimaitis 1, * , Lina Grauslyte 1 , Asta Zavackiene 1 , Vilda Baliuliene 1 ,
Ruta Nadisauskiene 2 and Andrius Macas 1
1 Department of Anaesthesiogy, Lithuanian University of Health Sciences, Eiveniu˛ str. 2,
LT-50009 Kaunas, Lithuania; lgrauslyte@gmail.com (L.G.); zavackieneasta@gmail.com (A.Z.);
vilda.cesnovaite@gmail.com (V.B.); andrius.macas@kaunoklinikos.lt (A.M.)
2 Department of Obstetrics and Gynecology, Lithuanian University of Health Sciences, Eiveniu˛ str. 2,
LT-50009 Kaunas, Lithuania; ruta.nadisauskiene@gmail.com
* Correspondence: kestutis.rimaitis@kaunoklinikos.lt; Tel.: +370-687-25347




Received: 13 November 2018; Accepted: 28 December 2018; Published: 3 January 2019


Abstract: HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet count) syndrome is a severe
and rapidly progressing condition that requires distinct diagnostic considerations. The aim of this
study was to evaluate the impact of the Mississippi triple-class system on the HELLP syndrome
diagnosis, treatment, and outcomes in a perinatology centre during a 10-year period, and consider
its effectiveness and necessity in everyday practice. A retrospective observational cohort study
was carried out using the medical records of a tertiary perinatology centre with the diagnosis of
HELLP syndrome from the period of time between 2005 and 2014. The patients who fit the HELLP
syndrome diagnosis were grouped by the Mississippi triple-class system. The means of diagnosis
and treatment outcomes within those groups were analysed statistically. There was insufficient
statistical evidence of the blood pressure levels corresponding to the severity of patients’ condition
(p > 0.05 in all of the groups). The clinical presentation varied within all of the classes, and the only
objective means of diagnosis and evaluation of progression of the condition were laboratory tests.
Even though HELLP syndrome is considered a hypertensive multi-organ disorder of pregnancy,
the level of hypertension does not correlate to the severity of the condition; hence, the diagnosis
should be based on biochemical laboratory evidence. Vigilance in suspicion and the recognition of
HELLP syndrome and appropriate treatment are essential in order to ensure better maternal and
neonatal outcomes.

Keywords: HELLP syndrome; pregnancy-related hypertension; Mississippi protocol; diagnostic criteria

1. Introduction
Hypertensive disorders of pregnancy complicate up to 10% of pregnancies and constitute one of
the major causes of maternal and perinatal morbidity and mortality worldwide [1]. HELLP (Hemolysis,
Elevated Liver enzymes, Low Platelet count) syndrome is a potentially life-threatening condition
manifesting in the context of preeclampsia, which poses challenging diagnostic and management
issues to the clinician [2]. At present, two major guidelines are used for HELLP syndrome diagnosis
based on haemolysis, elevated liver enzymes, and low platelet (PLT) count, namely, the Tennessee
classification and Mississippi triple-class system. According to the Mississippi triple-class system, the
severity of HELLP syndrome is mostly characterised by the amount of PLT (Table 1) [3,4]. However,
there is still a limited number of studies that would reveal the impact of the guideline application in
everyday practice. There is also very limited observational data on the effect that the diagnostics and
management approach has on the outcome on a larger scale. The aim of this study was to evaluate

Int. J. Environ. Res. Public Health 2019, 16, 109; doi:10.3390/ijerph16010109 www.mdpi.com/journal/ijerph
Int. J. Environ. Res. Public Health 2019, 16, 109 2 of 9

the impact of the Mississippi triple-class system on the HELLP syndrome diagnosis, treatment, and
outcomes in a perinatology centre during a 10-year period, and consider its effectiveness and necessity
in everyday practice.

Table 1. HELLP syndrome: Mississippi triple-class system [3].

HELLP Class Mississippi Classification

PLT (µL) ≤ 50,000
1 AST or ALT ≥ 70 IU/L
Total LDH ≥ 600 IU/L
50,000> PLT (µL) ≤ 100,000
2 AST or ALT ≥ 70 IU/L
Total LDH ≥ 600 IU/L
100,000> PLT (µL) ≤ 150,000
3 AST or ALT ≥ 40 IU/L
Total LDH ≥ 600 IU/L
Evidence of severe preeclampsia–eclampsia in association with
Partial HELLP syndrome
two of three laboratory criteria for HELLP syndrome
HELLP: Hemolysis, Elevated Liver enzymes, Low Platelet count, PLT: low platelet, AST: aspartate aminotransferase,
ALT: alanine aminotrasferase, LDH: lactate dehydrogenase.

2. Materials and Methods

This retrospective observational cohort study was carried out in a teaching hospital. No medical
interventions were implemented during the study period, approval to access medical records was
granted by the Lithuanian Medical Ethics commitee (No. BEC-MF-810). Medical records of all the
women with the diagnosis of HELLP syndrome that were treated during the 10-year period between
2005 and 2014 were reviewed. Parturients were allocated to HELLP (HELLP Class 1, Class 2, and Class 3
subgroups), and partial HELLP groups based on Mississippi triple-class system diagnostic criteria.
Cases that did not meet the HELLP nor partial HELLP syndrome criteria were excluded from the
study. Investigation of the medical records was carried out by three experienced physicians, who
work in an OB/GYN (obstetric/gynaecology) anaesthesiology and intensive care unit in the university
hospital. Data were analysed statistically using IBM SPSS 20.0 package (IBM Corp., Armonk, NY, USA).
The distribution for normality was evaluated by the Shapiro–Wilk test. Based on the results, the data
was further assessed using the Kruskal–Wallis and Mann–Whitney U-tests (for the non-normally and
normally distributed data, respectively). The significance level was set at 5% (p = 0.05).

3. Results
Between 2005 and 2014, there were 32,619 live births in our perinatology centre. Initially, according
to medical records, a total of 64 patients were found to have been diagnosed with HELLP syndrome
during the 10-year period. Following a detailed review of those records, 11 (17.19%) of parturients
were excluded from the study, as they did not meet the criteria for HELLP nor partial HELLP syndrome
diagnosis. The remaining 53 patients were included in the analysis, and 34 (65.4%) of them were
classified as the HELLP group, whereas the remaining 19 (34.6%) fit the criteria for the partial HELLP
syndrome group. All of the patients were Caucasian. The remaining demographic data and data
regarding mode of delivery of all of the study parturients are presented in Table 2.
It should be noted that within the HELLP group on admission, based on the Mississippi triple-class
system, five (14.7%) women fit the criteria of Class 1, 16 (47.1%) fit the criteria of Class 2, and 13 (38.2%)
fit the criteria of Class 3 HELLP syndrome. In 13 cases, the patients’ symptoms and laboratory test
results worsened, resulting in 12 (35.3%) patients with Class 1 and 16 (47.1%) with Class 2 HELLP
syndrome (as shown in Figure 1).
 Variable Class 1 Class 2 Class 3 HELLP HELLP
n = 12 (35.3%) n = 16 (47.1%) n = 6 (17.6%) n = 34 n = 19

Age 28 ± 4.9 28 ± 5.9 29 ± 5.6 28 ± 5.6 32 ± 6.9

Primigravida
Int. J. Environ. Res. Public Health 2019,816,
(66.7%)
109 10 (62.5%) 3 (50%) 21 (61.8%) 9 (47.4%)3 of 9

Primipara 9 (75%) 11 (68.8%) 3 (50%) 23 (67.6%) 10 (52.6%)

Table 2. Demographic and data regarding delivery of all of the patient groups.
Average gestational age
35 ± 4.0 32 ± 5.1 34 ± 4.6 33 ± 4.6 33 ± 3.9
at delivery HELLP HELLP HELLP Total Partial
Variable Class 1 Class 2 Class 3 HELLP HELLP
Prior to the 27th week n = 121 (35.3%)
(8.3%) n =216(12.5%)
(47.1%) 0 6(0%)
n= (17.6%) 3 (8.8%)
n = 34 2 (10.5%)
n = 19
Age 28 ± 4.9 28 ± 5.9 29 ± 5.6 28 ± 5.6 32 ± 6.9
27th–37th 6 (50%) 9 (56.3%) 5 (83.3%) 20 (58.8%) 15 (78.9%)
Primigravida 8 (66.7%) 10 (62.5%) 3 (50%) 21 (61.8%) 9 (47.4%)
After the 37th week
Primipara 94(75%)
(33.3%) 113 (68.8%)
(18.8%) 1 (16.7%)
3 (50%) 8 (23.5%)
23 (67.6%) 2 10
(10.5%)
(52.6%)
Average gestational
Postpartum 351±(8.3%)
4.0 2 (12.5%)
32 ± 5.1 034(0%)
± 4.6 3 (8.8%)
33 ± 4.6 033(0%)
± 3.9
age at delivery
Severe
Prior preeclampsia
to the 27th week 112 (100%)
(8.3%) 215(12.5%)
(93.8%) 6 (100%)
0 (0%) 33 (97.1%)
3 (8.8%) 192(100%)
(10.5%)
27th–37th 6 (50%) 9 (56.3%) 5 (83.3%) 20 (58.8%) 15 (78.9%)
Eclampsia 1 (8.3%) 1 (6.3%) 0 (0%) 2 (5.9%) 1 (5.3%)
After the 37th week 4 (33.3%) 3 (18.8%) 1 (16.7%) 8 (23.5%) 2 (10.5%)
Route of delivery:
Postpartum 1 (8.3%) 2 (12.5%) 0 (0%) 3 (8.8%) 0 (0%)
Severe preeclampsia 12 (100%) 15 (93.8%) 6 (100%) 33 (97.1%) 19 (100%)
Vaginal 4 (33.3%) 5 (31.2%) 2 (33.3%) 11 (32.4%) 9 (47.4%)
Eclampsia 1 (8.3%) 1 (6.3%) 0 (0%) 2 (5.9%) 1 (5.3%)
RouteCaesarean
of delivery: 8 (66.7%) 11 (68.8%) 4 (66.7%) 23 (67.6%) 10 (52.6%)
Vaginal 4 (33.3%) 5 (31.2%) 2 (33.3%) 11 (32.4%) 9 (47.4%)
Anaesthesia
Caesareantechnique: 8 (66.7%) 11 (68.8%) 4 (66.7%) 23 (67.6%) 10 (52.6%)
Anaesthesia technique:
Spinal
Spinal 1 (12.5%)
1 (12.5%) 44(36.4%)
(36.4%) 2 2(50%)
(50%) 7 (30.4%)
7 (30.4%) 2 2(20%)
(20%)
General 7 (87.5%) 7 (63.6%) 2 (50%) 16 (69.6%) 8 (80%)
General 7 (87.5%) 7 (63.6%) 2 (50%) 16 (69.6%) 8 (80%)

Figure 1. Initial
Figure presentation
1. Initial andand
presentation progression of severity
progression of the
of severity condition.
of the condition.

Clinical symptoms, mean highest systolic and diastolic blood pressure measures, and their
distribution among HELLP and partial HELLP groups are presented in Table 3, along with the
treatment administered before delivery. Figures 2–4 reflect the dynamic changes of the main laboratory
tests. In some cases, data regarding laboratory values, repeat tests, and other diagnostic information
was missing, which is apparent in the figures. Complications of all of the study group parturients are
presented in Table 4.
Int. J. Environ. Res. Public Health 2019, 16, 109 4 of 9

Table 3. Distribution of clinical symptoms, mean arterial blood pressures before and after delivery, and
treatment administered before delivery in HELLP and partial HELLP groups.

HELLP HELLP HELLP Total Partial

Variable Class 1 Class 2 Class 3 HELLP HELLP p Value
n = 12 (35.3%) n = 16 (47.1%) n = 6 (17.6%) n = 34 n = 19
Symptoms:
Headache 0 (0%) 5 (31.2%) 1 (16.7%) 6 (17.6%) 7 (36.8%) 0.037
Epigastric pain 8 (66.7%) 6 (37.5%) 3 (50%) 17 (50%) 8 (42.1%) 0.604
Generalised edema 3 (25%) 2 (12.5%) 0 (0%) 5 (14.7%) 4 (21.1%) 0.302
Nausea/vomiting 5 (41.7%) 5 (31.2%) 3 (50%) 13 (38.2%) 9 (21.1%) 0.965
Visual disturbances 1 (12.5%) 1 (6.3%) 1 (16.7%) 3 (8.8%) 2 (10.5%) 0.916
Highest BP before 168 ± 21/ 174 ± 34/ 152 ± 23/ 168 ± 28/ 177 ± 31/
0.462/0.945
delivery, S/D 105 ± 15 105 ± 21 97 ± 16 104 ± 18 101 ± 14
Highest BP after 163 ± 13/ 155 ± 26/ 147 ± 22/ 157 ± 21/ 151 ± 25/
0.349/0.130
delivery, S/D 97 ± 15 97 ± 18 85 ± 10 96 ± 16 90 ± 14
Antihypertensive
12 (100%) 16 (100%) 6 (100%) 34 (100%) 17 (89.5%)
medication
Magnesium sulfate 12 (100%) 15 (93.8%) 6 (100%) 33 (97.1%) 17 (89.5%)
Corticosteroids 100% of cases with gestational age between 24 and 35 weeks
BP—arterial blood pressure, S/D—systolic/diastolic.

Table 4. Prevalence of complications in all study groups.

HELLP HELLP HELLP Total Partial

Complication Class 1 Class 2 Class 3 HELLP HELLP
n = 12 (35.3%) n = 16 (47.1%) n = 6 (17.6%) n = 34 n = 19
Partial placental abruption 2 (16.7%) 1 (6.3%) 2 (33.3%) 5 (14.7%) 0 (0%)
Hepatic and renal failure 2 (16.7%) 1 (6.3%) 0 (0%) 3 (8.8%) 0 (0%)
Intracerebral hemorrhage 1 (8.3%) 0 (0%) 0 (0%) 1 (2.9%) 1 (5.3%)
Int. J. Environ. Res.death
Perinatal Public Health 2019, 16, x FOR PEER REVIEW
1 (8.3%) 3 (18.8%) 1 (16.7%) 5 (14.7%) 5 of 10
0 (0%)

Figure 2. Dynamic changes of platelet count; PLT—platelet count.

Figure 2. Dynamic changes of platelet count; PLT—platelet count.
Int. J. Environ. Res. Public Figure
Health 2019, 16, 109 changes of platelet count; PLT—platelet count.
2. Dynamic 5 of 9

Int. J. Environ. Res. Public Health 2019, 16, x FOR PEER REVIEW 6 of 10
Figure 3. Dynamic changes of blood aspartate aminotransferase levels; AST—aspartate aminotransferase.
Figure 3. Dynamic changes of blood aspartate aminotransferase levels; AST—aspartate aminotransferase.

Figure 4. Dynamic changes of blood lactate dehydrogenase levels; LDH—lactate dehydrogenase.

Figure 4. Dynamic changes of blood lactate dehydrogenase levels; LDH—lactate dehydrogenase.
The average diagnosis-to-delivery time in the HELLP group for patients who were admitted
Thetoaverage
directly diagnosis-to-delivery
our hospital time
or were transferred in other
from the HELLP
hospitalsgroup for differ
did not patients who wereand
significantly, admitted
was at
directly to our hospital or were transferred from other hospitals did not differ significantly,
6.4 h (95% CI, 3.6 to 9.2, standard error of mean (SEM) = 1.41) and 6.8 h (95% CI, 3.8 to 10.6, SEM = 1.93),and was
at 6.4 h (95% CI, 3.6 to 9.2, standard error of mean (SEM) = 1.41) and 6.8 h (95% CI, 3.8
respectively. The average admittance-to-delivery time was 9.5 h (95% CI, 6.2 to 12.8, SEM = 1.67) forto 10.6, SEM =
1.93), respectively. The average admittance-to-delivery time was 9.5 h (95% CI, 6.2
the HELLP syndrome patients who were admitted directly to our hospital, and 21.9 h (95% CI, 9.2 to to 12.8, SEM =
1.67)
34.6, for
SEM the
= HELLP syndrome
6.5) for the patients
transferred who were
patients; admitted
however, directly to
the difference ournot
was hospital, and 21.9
statistically h (95%
significant.
CI, 9.2 to 34.6, SEM = 6.5) for the transferred patients; however, the difference was
The average diagnosis-to-delivery and admittance-to-delivery time in the partial HELLP group had nonot statistically
significant. The averagebased
significant differences diagnosis-to-delivery and admittance-to-delivery
on the primary location of the patient. In alltime ingroups
of the the partial HELLP
during this
group had no significant differences based on the primary location of the patient. In all of the groups
during this time, hypertension control, foetal lung maturation, and other measures aiming to prepare
the mother and the foetus for delivery were taken.

4. Discussion
Int. J. Environ. Res. Public Health 2019, 16, 109 6 of 9

time, hypertension control, foetal lung maturation, and other measures aiming to prepare the mother
and the foetus for delivery were taken.

4. Discussion
It is evident that the wide variety of possible clinical presentations of HELLP syndrome makes the
clinical symptoms unreliable diagnostic criteria. Not only is it difficult to assess whether the severity
of the patient’s condition can be predicted based on their subjective complaints, HELLP syndrome in
its clinical presentation is similar to other conditions, such as benign thrombocytopenia of pregnancy,
acute fatty liver of pregnancy, viral hepatitis, and others [5–9]. The symptoms of our study patients
corresponded well with those described as most common in other studies [10–13]. It is of note that they
did not in any way represent the severity of patients’ condition, and did not significantly influence
the making of the final diagnosis, further highlighting the key role that laboratory tests play in the
differential diagnosis of this condition. However, considering that there are certain tendencies in the
clinical presentation of HELLP syndrome, all of the aforementioned symptoms should be noted in the
diagnosis process, because they serve as “red flags” allowing clinicians to suspect HELLP syndrome in
the first place.
The HELLP or partial HELLP syndrome diagnosis can be made during pregnancy or postpartum
in women who were diagnosed with pregnancy-related hypertension (increase in the arterial blood
pressure first detected after 20 weeks of gestation), with or without proteinuria. Despite many authors
having shown that HELLP syndrome is a complication of preeclampsia or eclampsia, Sibai and Martin
et al. observed that hypertension and proteinuria may be absent or only slight [14]. In our study, there
was insufficient statistical evidence that the increased level of arterial blood pressure prior to delivery
in all four groups (Class 1, Class 2, Class 3, and partial HELLP) correlates with the severity of HELLP
syndrome (p > 0.05 in all groups). Hence, while arterial blood pressure is one of the main criteria in
the diagnosis and treatment of preeclampsia, it is not as informative in the case of HELLP syndrome,
and should not be used to predict its progression. It is important to recognise HELLP syndrome as a
distinct entity that is associated with serious maternal morbidity [14].
Some authors have suggested intravenous dexamethasone as treatment to raise platelet counts
and improve liver function test abnormalities [15]. The administration of intravenous corticosteroids
antepartum remains a controversial approach to HELLP syndrome treatment. There are studies [16,17]
that suggest that there is no benefit to the aforementioned treatment. However, the validity of
these studies and their study design has been called into question by both Martin et al. and
O’Brien [13,18]. Other studies have claimed that following the Mississippi protocol regarding
intravenous dexamethasone administration allows clinicians to achieve four of the five goals: absence
of maternal mortality, a reduction of major maternal morbidity (<20% in Class 1 and <5% in
Class 2), a low rate of Class 3 or Class 2 HELLP syndrome progression to Class 1, and a mean
length of hospitalisation following delivery of only four to 4.5 days [19]. However, there are no
statistically and scientifically valid prospective randomised studies regarding this component of
antepartum management due to ethical issues, rendering intravenous dexamethasone administration
an individual medical institution protocol decision. In our hospital, since 2012, in the majority of cases,
IV dexamethasone has been used in regard to thrombocytopenia as well as foetal lung maturation.
Therefore, it remains unclear which criteria in which cases were the determining factors in choosing or
forgoing the treatment with IV dexamethasone during the whole 10-year period of the study. Hence,
it is difficult to analyse the effectiveness of the treatment strategy before delivery and its impact on
the final outcomes. Failure to have a standardised treatment protocol not only makes it difficult to
provide urgent care in the case of HELLP syndrome, it also makes it virtually impossible to compare
treatment results between different studies, therefore showing the necessity of the implementation of
both diagnostic and treatment protocols and guidelines.
Int. J. Environ. Res. Public Health 2019, 16, 109 7 of 9

It is advised to arrange the delivery within 24–48 h after the diagnosis is made [12,20].
Preeclampsia increases the cesarean rate, which ranges from 29.6% to 55.0%, with the percentage
always being significantly higher than the incidence of cesareans among healthy pregnant women
or pregnant women with isolated chronic hypertension [14]. In our hospital, in case of full-term
pregnancy, the induction of vaginal delivery is the preferred approach, and in pre-term cases with an
immature cervix, caesarean section is performed. In our study, 23 (67.6%) cases of HELLP syndrome
ended in caesarean section. It should be taken into consideration that five women were diagnosed
with placental abruption, while 23 (67.6%) of the deliveries were pre-term, and the majority of the
patients had severe preeclampsia; therefore, it is difficult to determine whether the diagnosis of HELLP
syndrome played the main role in choosing the route of delivery.
The occurrence rates of maternal and foetal HELLP syndrome complications in our study were
consistent with those reported in other major studies [21–23]. Sadly, the data to assess the rate of acute
kidney injury was not collected, as it seems to be associated with the rate of HELLP syndrome and have
a correlation with further complications [24]. The perinatal mortality rate in our study was also within
the ranges suggested by other studies [25–29]. There were no maternal deaths during our study period,
once again proving that following the diagnostic protocol and treatment time, recommendations can
help in reducing both perinatal and maternal complication and mortality rates.
Recently, an increasing number of articles have been published regarding the pathophysiology of
HELLP syndrome, and there have been more and more studies aiming to find a laboratory marker
that could possibly help diagnose HELLP syndrome early and objectively. There is research that
provides promising new options such as the Elecsys immunoassay sFlt-1/PlGF (fms-like tyrosine
kinase 1/placental growth factor) ratio [30] or using the modified Ham test [31]. However, it has to
be kept in mind, that thus far none of the new options have been approved, as they still lack both
sensitivity and specificity.
Certain difficulties arise when trying to compare clinical studies and reports regarding HELLP
syndrome. Up until now, HELLP syndrome has had many different definitions, classifications,
and criteria that have been used by fellow clinicians and scientists. This has limited the usefulness
of many clinical reports. The Tennessee and Mississippi classifications are well-suited to facilitate
comparisons. Classifications used in future reports should be restricted to one of these [24]. Using
similar terms and being able to compare data should allow us to gain better understanding of the
condition and in turn facilitate successful treatment.

5. Conclusions
HELLP syndrome is a potentially life-threatening dynamic condition for which a standardised
approach to diagnosis and management is paramount. Even though HELLP syndrome is considered a
hypertensive multi-organ disorder of pregnancy, the level of hypertension does not correlate to the
severity of the condition; hence, the diagnosis should be based on biochemical laboratory evidence.
It should be kept in mind that clinical presentation is one of the main factors that allow the timely
diagnosis of this condition. Considering all of these factors, the implementation of standardised
diagnostic criteria based on laboratory findings such as the Mississippi triple-class system for HELLP
syndrome creates a possibility of defining this disorder similarly in most cases, applying the same
treatment options in the same stage of the condition, and improving maternal and perinatal outcomes.

Author Contributions: Conceptualisation K.R., A.Z.; Methodology A.Z., L.G., V.B.; Software L.G.; Validation
L.G., V.B.; Formal analysis A.Z., L.G.; Investigation L.G., A.Z., V.B.; Resources A.M.; Data curation A.Z., K.R.;
Writing—original draft preparation, L.G., A.Z.; Writing—review and editing K.R., R.N., A.M.; Visualization, L.G.;
Supervision K.R.; Project administration A.M., K.R.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
Int. J. Environ. Res. Public Health 2019, 16, 109 8 of 9

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